Effect of Maraviroc Intensification on HIV-1-Specific T Cell Immunity in Recently HIV-1-Infected Individuals

Background

The effect of maraviroc on the maintenance and the function of HIV-1-specific T cell responses remains unknown.

Methods

Subjects recently infected with HIV-1 were randomized to receive anti-retroviral treatment with or without maraviroc intensification for 48 weeks, and were monitored up to week 60. PBMC and in vitro-expanded T cells were tested for responses to the entire HIV proteome by ELISpot analyses. Intracellular cytokine staining assays were conducted to monitor the (poly)-functionality of HIV-1-specific T cells. Analyses were performed at baseline and week 24 after treatment start, and at week 60 (3 months after maraviroc discontinuation).

Results

Maraviroc intensification was associated with a slower decay of virus-specific T cell responses over time compared to the non-intensified regimen in both direct ex-vivo as well as in in-vitro expanded cells. The effector function profiles of virus-specific CD8⁺ T cells were indistinguishable between the two arms and did not change over time between the groups.

Conclusions

Maraviroc did not negatively impact any of the measured parameters, but was rather associated with a prolonged maintenance of HIV-1-specific T cell responses. Maraviroc, in addition to its original effect as viral entry inhibitor, may provide an additional benefit on the maintenance of virus-specific T cells which may be especially important for future viral eradication strategies.     

Geographical Variability in the Likelihood of Bloodstream Infections Due to Gram-Negative Bacteria: Correlation with Proximity to the Equator and Health Care Expenditure

ObjectiveInfections due to Gram-negative bacteria exhibit seasonal trends, with peak infection rates during warmer months. We hypothesized that the likelihood of a bloodstream infection due to Gram-negative bacteria increases with proximity to the equator. We tested this hypothesis and identified geographical, climatic and social factors associated with this variability.DesignWe established a network of 23 international centers in 22 cities. Setting: De-identified results of positive blood cultures from 2007–2011 and data sources for geographic, climatic and socioeconomic factors were assembled for each center.ParticipantsPatients at the 23 centers with positive blood cultures.ResultsThe mean fraction of bacteremia associated with Gram-negative bacteria was 48.4% (range 26.4% to 61.8%). Although not all sites displayed significant seasonality, the overall P-value for seasonal oscillation was significant (P<0.001). In univariate meta-regression models, temperature, latitude, latitude squared, longitude, per capita gross domestic product and percent of gross domestic product spent on healthcare were all associated with the fraction of bacteremia due to Gram-negative bacteria. In multivariable models, only percent of gross domestic product spent on healthcare and distance from the equator (ie. latitude squared) were significantly associated with the fraction of bacteremia due to Gram-negative bacteria.ConclusionsThe likelihood of bacteremia due to Gram-negative bacteria varies markedly between cities, in a manner that appears to have both geographic (latitude) and socioeconomic (proportion gross domestic product devoted to health spending) determinants. Thus, the optimal approach to initial management of suspected bacteremia may be geographically specific. The rapid emergence of highly antibiotic-resistant Gram-negative pathogens may have geographically specific impacts.     

Longitudinal Analysis Is More Powerful than Cross-Sectional Analysis in Detecting Genetic Association with Neuroimaging Phenotypes

Most existing genome-wide association analyses are cross-sectional, utilizing only phenotypic data at a single time point, e.g. baseline. On the other hand, longitudinal studies, such as Alzheimer''s Disease Neuroimaging Initiative (ADNI), collect phenotypic information at multiple time points. In this article, as a case study, we conducted both longitudinal and cross-sectional analyses of the ADNI data with several brain imaging (not clinical diagnosis) phenotypes, demonstrating the power gains of longitudinal analysis over cross-sectional analysis. Specifically, we scanned genome-wide single nucleotide polymorphisms (SNPs) with 56 brain-wide imaging phenotypes processed by FreeSurfer on 638 subjects. At the genome-wide significance level () or a less stringent level (e.g. ), longitudinal analysis of the phenotypic data from the baseline to month 48 identified more SNP-phenotype associations than cross-sectional analysis of only the baseline data. In particular, at the genome-wide significance level, both SNP rs429358 in gene APOE and SNP rs2075650 in gene TOMM40 were confirmed to be associated with various imaging phenotypes in multiple regions of interests (ROIs) by both analyses, though longitudinal analysis detected more regional phenotypes associated with the two SNPs and indicated another significant SNP rs439401 in gene APOE. In light of the power advantage of longitudinal analysis, we advocate its use in current and future longitudinal neuroimaging studies.     

The Effect of Dosing Regimens on the Antimalarial Efficacy of Dihydroartemisinin-Piperaquine: A Pooled Analysis of Individual Patient Data

Background

Dihydroartemisinin-piperaquine (DP) is increasingly recommended for antimalarial treatment in many endemic countries; however, concerns have been raised over its potential under dosing in young children. We investigated the influence of different dosing schedules on DP''s clinical efficacy.

Methods and Findings

A systematic search of the literature was conducted to identify all studies published between 1960 and February 2013, in which patients were enrolled and treated with DP. Principal investigators were approached and invited to share individual patient data with the WorldWide Antimalarial Resistance Network (WWARN). Data were pooled using a standardised methodology. Univariable and multivariable risk factors for parasite recrudescence were identified using a Cox''s regression model with shared frailty across the study sites. Twenty-four published and two unpublished studies (n = 7,072 patients) were included in the analysis. After correcting for reinfection by parasite genotyping, Kaplan–Meier survival estimates were 97.7% (95% CI 97.3%–98.1%) at day 42 and 97.2% (95% CI 96.7%–97.7%) at day 63. Overall 28.6% (979/3,429) of children aged 1 to 5 years received a total dose of piperaquine below 48 mg/kg (the lower limit recommended by WHO); this risk was 2.3–2.9-fold greater compared to that in the other age groups and was associated with reduced efficacy at day 63 (94.4% [95% CI 92.6%–96.2%], p<0.001). After adjusting for confounding factors, the mg/kg dose of piperaquine was found to be a significant predictor for recrudescence, the risk increasing by 13% (95% CI 5.0%–21%) for every 5 mg/kg decrease in dose; p = 0.002. In a multivariable model increasing the target minimum total dose of piperaquine in children aged 1 to 5 years old from 48 mg/kg to 59 mg/kg would halve the risk of treatment failure and cure at least 95% of patients; such an increment was not associated with gastrointestinal toxicity in the ten studies in which this could be assessed.

Conclusions

DP demonstrates excellent efficacy in a wide range of transmission settings; however, treatment failure is associated with a lower dose of piperaquine, particularly in young children, suggesting potential for further dose optimisation. Please see later in the article for the Editors'' Summary     

Relationships of hepatic and pancreatic biomarkers with the cholestatic syndrome and tumor stage in pancreatic cancer

We analyzed relationships of hepatic and pancreatic biomarkers with the cholestatic syndrome and tumor stage in exocrine pancreatic cancer (N = 183). Information on laboratory tests and on signs and symptoms was obtained from medical records and patient interviews. Bilirubin, aspartate aminotransferase (AST), γ-glutamyltransferase (GGT) and alkaline phosphatase were lower in tumor stage IV. The association was due to the relationship between cholestatic syndrome and earlier presentation of patients. There was no association between hepatic biomarkers and stage when adjusting by cholestatic syndrome. Relationships of hepatic and pancreatic biomarkers with pancreatic symptoms and tumor stage must be controlled in “-omics” and other studies using biomarkers.     

Impact of cardiovascular risk factors on oxidative stress and DNA damage in a high risk Mediterranean population

Abstract

The impact of classic cardiovascular risk factors on oxidative stress status in a high-risk cardiovascular Mediterranean population of 527 subjects was estimated. Oxidative stress markers (malondialdehyde, 8-oxo-7′8′-dihydro-2′-deoxyguanosine, oxidized/reduced glutathione ratio) together with the activity of antioxidant enzyme triad (superoxide dismutase, catalase, glutathione peroxidase) were analysed in circulating mononuclear blood cells. Malondialdehyde, oxidized glutathione and the ratio of oxidized to reduced glutathione were significantly higher while catalase and glutathione peroxidase activities were significantly lower in high cardiovascular risk participants than in controls. Statistically significant differences were obtained after additional multivariate control for sex, age, obesity, diabetes, lipids and medications. Among the main cardiovascular risk factors, hypertension was the strongest determinant of oxidative stress in high risk subjects studied at a primary prevention stage.     

Genome‐wide linkage analysis for human longevity: Genetics of Healthy Aging Study

Clear evidence exists for heritability of human longevity, and much interest is focused on identifying genes associated with longer lives. To identify such longevity alleles, we performed the largest genome‐wide linkage scan thus far reported. Linkage analyses included 2118 nonagenarian Caucasian sibling pairs that have been enrolled in 15 study centers of 11 European countries as part of the Genetics of Healthy Aging (GEHA) project. In the joint linkage analyses, we observed four regions that show linkage with longevity; chromosome 14q11.2 (LOD = 3.47), chromosome 17q12‐q22 (LOD = 2.95), chromosome 19p13.3‐p13.11 (LOD = 3.76), and chromosome 19q13.11‐q13.32 (LOD = 3.57). To fine map these regions linked to longevity, we performed association analysis using GWAS data in a subgroup of 1228 unrelated nonagenarian and 1907 geographically matched controls. Using a fixed‐effect meta‐analysis approach, rs4420638 at the TOMM40/APOE/APOC1 gene locus showed significant association with longevity (P‐value = 9.6 × 10^?8). By combined modeling of linkage and association, we showed that association of longevity with APOEε4 and APOEε2 alleles explain the linkage at 19q13.11‐q13.32 with P‐value = 0.02 and P‐value = 1.0 × 10^?5, respectively. In the largest linkage scan thus far performed for human familial longevity, we confirm that the APOE locus is a longevity gene and that additional longevity loci may be identified at 14q11.2, 17q12‐q22, and 19p13.3‐p13.11. As the latter linkage results are not explained by common variants, we suggest that rare variants play an important role in human familial longevity.     

Cytomegalovirus infection is associated with increased mortality in the older population

Cytomegalovirus (CMV) is a common herpesvirus infection and stimulates the expansion of very large numbers of CMV‐specific T cells that reduce the CD4/CD8 ratio and suppress the number of naïve T cells. CMV infection has been associated with frailty and impaired survival. We investigated the correlates of CMV and the impact of the CMV infection on mortality within a cohort of 511 individuals aged at least 65 years who were followed up for 18 years. The mean age of the participants was 74 years of which 70% were CMV‐seropositive. CMV was strongly linked to socio‐economic status, and CMV infection increased the annual mortality rate by 42% (Hazard ratio = 1.42, 95% CI: 1.11–1.76 after adjusting for age, sex and baseline socio‐economic and health variables) corresponding to 3.7 years lower life expectancy from age 65. Infection was associated with a near doubling of cardiovascular deaths, whereas there was no increase in mortality from other causes. These results show that CMV infection markedly increases the mortality rate in healthy older individuals due to an excess of vascular deaths. These findings may have significant implications for the study of immune senescence and if confirmed more generally could have important implications for measures to optimize the health of the elderly.